The present invention relates to a process for diastereoselective reduction of 3-amino-1-benzoxepin-5(2H)-ones to 2,3,4,5-tetrahydro-3-amino-1-benzoxepin-5-ols in which the substituents in the 3- and 5-positions are predominantly cis to each other.
2,3,4,5-tetrahydro-3-amino-1-benzoxepin-5-ols and their acid addition salts are known from U.S. Pat. No. 4,279,904. These compounds have two asymmetric centers (C3 and C5, Cf. the following formula I) on which substituents in any given case may be arranged in the R- or the S-configuration, so that these substances occur in several stereoisomeric forms. These substances exhibit a pharmacological activity which has a favorable effect on gastrointestinal motility and are therefore useful as pharmaceuticals. In this respect cis-2,3,4,5-tetrahydro-3-amino-1-benzoxepin-5-ols, in which the substituents in the 3- and 5-positions are cis to each other, have proven to be especially suitable for oral application.
In accordance with the process described in U.S. Pat. No. 4,279,904, 2,3,4,5-tetrahydro-3-amino-1-benzoxepin-5-ols can be produced from the corresponding 3-amino-1-benzoxepin-5(2H)-ones by one stage or two stage reduction by treatment with specific hydride reducing agents and/or by catalytic hydrogenation in the presence of Raney nickel.
The single stage reduction is achieved with sodium borohydride in a neutral to weakly acid medium or with sodium cyanoborohydride in an acid medium or by catalytic hydrogenation in the presence of Raney nickel in a protic solvent. In these procedures mixtures of the different diastereoisomers are formed.
From such mixtures the racemate having the cis configuration or the racemate having the trans configuration must first be enriched and then finally isolated by means of expensive separating processes, e.g. fractional crystallization of suitable salts or chromatographic processes. The resulting racemic cis-2,3,4,5-tetrahydro-3-amino-1-benzoxepin-5-ol, which is substantially free of trans epimers, or the corresponding racemate with the trans configuration, which is substantially free of cis epimers, can subsequently be separated in a known manner into its optical isomers if desired.
In the two stage reduction process described in U.S. Pat. No. 4,279,904, the 3-amino-1-benzoxepin-5(2H)-one is first converted by hydrogenation of the 3,4-double bond into the corresponding 3-amino-3,4-dihydro-1-benzoxepin-5(2H)-one. This reaction may be achieved by catalytic hydrogenation in the presence of Raney-nickel in an aprotic solvent or by reaction with sodium cyanoborohydride in a weakly acid medium. The 5-keto group is then reduced in a second reduction stage to a hydroxy group. This reaction may be effected using the hydride reducing agents listed in U.S. Pat. No. 4,279,904. Only in this two stage reduction process is it possible to achieve in the second reduction stage an enrichment of cis-2,3,4,5-tetrahydro-3-amino-1-benzoxepin-5-ols in the reduction product by using a special selective hydride reducing agent which, however, is technically very expensive to work with.